5XYX

The structure of p38 alpha in complex with a triazol inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.61 Å
  • R-Value Free: 0.260 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

In Silico Identification of a Novel Hinge-Binding Scaffold for Kinase Inhibitor Discovery.

Wang, Y.Sun, Y.Cao, R.Liu, D.Xie, Y.Li, L.Qi, X.Huang, N.

(2017) J Med Chem 60: 8552-8564

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b01075
  • Primary Citation of Related Structures:  
    5XYX, 5XYY, 5XYZ

  • PubMed Abstract: 

    To explore novel kinase hinge-binding scaffolds, we carried out structure-based virtual screening against p38α MAPK as a model system. With the assistance of developed kinase-specific structural filters, we identify a novel lead compound that selectively inhibits a panel of kinases with threonine as the gatekeeper residue, including BTK and LCK. These kinases play important roles in lymphocyte activation, which encouraged us to design novel kinase inhibitors as drug candidates for ameliorating inflammatory diseases and cancers. Therefore, we chemically modified our substituted triazole-class lead compound to improve the binding affinity and selectivity via a "minimal decoration" strategy, which resulted in potent and selective kinase inhibitors against LCK (18 nM) and BTK (8 nM). Subsequent crystallographic experiments validated our design. These rationally designed compounds exhibit potent on-target inhibition against BTK in B cells or LCK in T cells, respectively. Our work demonstrates that structure-based virtual screening can be applied to facilitate the development of novel chemical entities in crowded chemical space in the field of kinase inhibitor discovery.


  • Organizational Affiliation

    National Institute of Biological Sciences, Beijing , No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 14380Homo sapiensMutation(s): 0 
Gene Names: MAPK14CSBPCSBP1CSBP2CSPB1MXI2SAPK2A
EC: 2.7.11.24
UniProt & NIH Common Fund Data Resources
Find proteins for Q16539 (Homo sapiens)
Explore Q16539 
Go to UniProtKB:  Q16539
PHAROS:  Q16539
GTEx:  ENSG00000112062 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ16539
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FTZ
Query on FTZ

Download Ideal Coordinates CCD File 
B [auth A]N-(2-chloro-6-fluorobenzyl)-5-(furan-2-yl)-2H-1,2,4-triazol-3-amine
C13 H10 Cl F N4 O
AHOHWELPUXLPOF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
FTZ BindingDB:  5XYX IC50: 1.44e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.61 Å
  • R-Value Free: 0.260 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.15α = 90
b = 86.13β = 90
c = 124.77γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
iMOSFLMdata reduction
SCALEPACKdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-01-17
    Type: Initial release
  • Version 1.1: 2018-05-23
    Changes: Data collection, Database references
  • Version 1.2: 2023-11-22
    Changes: Data collection, Database references, Refinement description